Toxicity of phosphate enemas - an updated review.

INTRODUCTION: Enemas containing phosphate are widely prescribed and may cause important adverse effects. A systemic review published in 2007 reported the literature on the adverse effects of phosphate enemas from January 1957 to March 2007 and identified 12 deaths. These were thought due to electrolyte disturbances, heart failure and kidney injury. These data raised concerns about the use of phosphate enemas in routine practice. Newer osmotic-based enema alternatives are now available that do not contain absorbable ions. We sought to review the literature since this review and evaluate the latest data on the toxicity of phosphate-containing enemas. To gain a fuller picture we included case series and larger studies as well as case reports. OBJECTIVES: To review the toxicity of phosphate enemas, particularly with respect to acute metabolic consequences and their associated clinical features. To identify risk factors for metabolic toxicity and consider whether phosphate enemas should be relatively contra-indicated in specific patient groups. METHODS: A systematic literature review was conducted in PubMed, Google Scholar, and Cochrane Reviews (2005-2021) using the search terms 'phosphate enema or sodium phosphate enema' or 'phosphate-based enema' or (phosphate AND enema) or (Fleet AND enema) or 'sodium phosphate laxatives' or 'sodium phosphate catharsis' or 'sodium phosphate cathartic'. Relevant papers were read, and data were extracted. RESULTS: The searches identified 489 papers of which 25 were relevant: seven papers were case reports or small case series of metabolic abnormalities from the use of phosphate enemas in nine children, six were case reports on 16 adults. Nine papers were large case series or clinical studies that included data on systemic metabolic effects, of varying size from 24 healthy volunteers to a cohort of 70,499 patients. Case reports identified seven adult deaths but none in children. Children most often presented with decreased consciousness (6/9), and tetany (4/9). In adults overall only five cases had clinical features reported, hypotension was seen in four and QT prolongation in two. Treatment was generally symptomatic, with intravenous fluid and calcium salts for electrolyte changes and hypocalcaemia, and vasopressors for severe hypotension. Haemodialysis was used in three children and peritoneal dialysis in one, all of whom survived. In adults, haemodialysis did not prevent death in two of four cases in whom it was used. Common factors underlying toxicity were inappropriately high phosphate dose, or enema retention, both resulting in greater absorption of phosphate. Associated pre-disposing conditions included Hirschsprung disease in children and co-morbidity and renal impairment (2/5) in older adults. Absolute reported changes in serum phosphate or calcium were not accurate indicators of outcome. Larger case series and clinical trials confirm an acute effect of phosphate enemas on serum phosphate, which was related to both dose and retention time. These effects were not seen with non-phosphate preparations. In these cases series, adverse events were rarely reported. CONCLUSION: Phosphate enemas are potentially toxic, particularly in young children with Hirschsprung disease and in the elderly with co-morbidity. Raised awareness of the risk of phosphate enemas is still required. Other less toxic enema preparations are available and should be considered in patients at extremes of age. If phosphate enemas are the only clinical option careful monitoring of biochemical sequelae should be undertaken.

Identification of rhein as the metabolite responsible for toxicity of rhubarb anthraquinones.

Rhubarb is a popular food in Europe with laxative properties attributed to anthraquinones. Long term usage of rhubarb anthraquinones has been linked to colonic toxicity, including the formation of melanosis coli, which is associated with increased risk of colon cancer. The major purgative anthraquinone in rhubarb is thought to be sennoside A, which is metabolised by colonic microflora. Here, we sought to identify the toxic metabolite responsible for melanosis coli in rats dosed with rhubarb anthraquinones for up to 90 days. Three metabolites were detected in rat faeces using HPLC. Of these, rhein was identified as the metabolite that accumulated most over time. Fecal flora from treated rats were capable of greater biotransformation of sennoside A to rhein compared to that from control rats. Cell culture experiments suggested that apoptosis and autophagy induced by rhein is the likely mechanism of chronic toxicity of rhubarb anthraquinones.

Morning glory seed keeps laxative effect while retains less subchronic toxicity after being fried.

ETHNOPHARMACOLOGICAL RELEVANCE: Morning glory seed (MGS), has been widely used in treating constipation especially towards children. Clinically, people usually take fried MGS (MGSF) in formulas to reduce its side effect. However, the safety of MGSF other than MGS has yet to be explored. OBJECTIVE: The study aimed to reveal the potential mechanisms of using MGSF instead of MGS basing on chemistry, pharmacodynamics and toxicology. METHODS: The chemical compositions of the extracts of MGS and MGSF were compared using UPLC-Q-TOF/MS method. Simultaneously, to prove the availability and safety of MGSF, we investigated the laxative effect and subchronic toxicity of MGS and MGSF and addressed the mechanism of laxative effect of them. RESULTS: In this study, less phenolic acids and more fatty acids were detected in MGSF compared with the compounds in MGS. Moreover, we found that MGS group had stronger laxative effect than MGSF group via downregulating the expression of AQP3 protein. As for subchronic toxicity test, the body weights of MGS group were lower than MGSF group. In serum biochemistry and histopathological examinations, MGS group could cause more serious toxicity in liver, kidney and colon than MGSF group with higher values of BUN, Cr, AST and ALP. CONCLUSION: Based on the findings in this study, MGSF with varied compounds contents could still keep the laxative effect while retain less subchronic toxicity, which emphasized the necessity of processing and provided an insight into the rational use of MGSF in clinical practice.

Toxicological implications and laxative potential of ethanol root extract of Morella serrata in loperamide-induced constipated Wistar rats.

CONTEXT: Morella serrata L. (Myricaceae) is commonly used in South Africa to treat several diseases including constipation. OBJECTIVES: This study investigated toxicological implications and laxative potential of the ethanol root extract of the plant. MATERIALS AND METHODS: While normal control animals were placed on sterile placebo, the loperamide-constipated rats were treated with the extract at 75, 150 and 300 mg/kg doses for 7 days, and their feeding patterns and faecal properties were monitored. Gastrointestinal transit ratio and the toxicity profile of the tested doses were thereafter evaluated. RESULTS: The significantly increased faecal volume (192.08%), feed (63.63%), water intake (55.97%) and improved intestinal motility (95.05%) in the constipated rats following treatment with the extract (at 300 mg/kg) suggested laxative potential of the extract. The 1.5-2.0-fold normalization of the platelets, erythrocytes and leukocytes counts in the extract-treated constipated rats suggests its non-haematotoxic tendency. Furthermore, the extract (at the highest investigated dose) reversed the attenuation in the concentrations of the electrolytes (0.5-2-fold), total protein (62.12%) and albumin (55.88%) in the constipated animals as well as attenuated activities of hepatic enzymes (0.5-3.0-fold) and levels of urea (126.67%), creatinine (40.32%), cholesterol (3-fold) and triglycerides (9-fold). These further support its non-toxic and therapeutic attributes against constipation. CONCLUSION: Overall, the effect exhibited by M. serrata in this study competed well with Senokot (standard drug) and proved that it may be relatively safe and with excellent laxative potential, thus, supporting its pharmacological applications in South Africa.

Phytochemical Characteristics of Seeds and Its Effects on the Intestinal Motility and Toxicity of Joannesia princeps.

Joannesia princeps is a plant commonly used in folk medicine as laxative for menstrual discomfort and as antihelminthic and antimicrobial to reduce edema and improve tissue healing. The seeds are used in many regions of Brazil as laxative; however, studies are needed to confirm its effectiveness and safety. Thus, the aim of this study was to evaluate the effects of using seeds of this plant on intestinal motility of Wistar rats, evaluate the effects and acute toxicity of its management, as well as determine its phytochemical profile. The evaluation of the effect on the intestinal motility was performed according to the model described by Michelin and Salgado (2004) with modifications. For the evaluation of acute toxicity, we used the model described by Craveiro et al. (2008) and Goloni et al. (2005), and for the analysis of the presence of alkaloids, flavonoids, anthraquinones, steroids, and other components, we used the method described by Carvalho et al. (2006). The results showed that J. princeps exhibits laxative effects similar to those of Senna species such as Cassia angustifolia and the phytochemical analysis of ethanol and aqueous extracts showed the presence of alkaloids, triterpenes, and/or steroids compounds. Acute toxicity showed in the first 12 h: piloerection, contortion, decreased respiratory rate, diarrhea, and weight loss. After this period, these changes were no longer observed. It was concluded that the seeds of this plant have potential laxative activity, confirming the popular use and that the dose of 5 g/kg can be considered safe for consumption.

Toxicity and antioxidant capacity of Frangula alnus Mill. bark and its active component emodin.

In the present study toxicity of Frangula alnus Mill. bark, widely used as laxative, was investigated. Human peripheral blood lymphocytes (HPBLs) were treated with F. alnus bark extract or emodin (emodin is bark component with laxative property), and cytotoxicity, genotoxicity and parameters of oxidative stress were assessed. Also, polyphenol content of bark extract and antioxidant activity of the extract and emodin measured by DPPH, ABTS and FRAP methods were examined. The bark extract (500 µg/ml) produced cell death and DNA damage, while level of ROS changed at 250 µg/ml. Emodin induced cell death and DNA damage at 150 µg/ml and 200 µg/ml, respectively, and the increase of ROS was observed at 25 µg/ml. These results suggest that both, bark extract and emodin, are cyto/genotoxic to HPBLs and that oxidative stress is involved in the mechanism of their toxicity. The results on antioxidant activity showed that, unlike emodin, bark extract possess moderate antioxidant capacity (44.6%, 46.8% and 2.25 mmol Fe(2+)/g measured by DPPH, ABTS and FRAP assay, respectively) that can be related to relatively high phenolic content (116.07 mg/g). However, due to toxicological properties use of F. alnus bark as well as emodin-containing preparations should be taken with caution.

Pharmacological basis for the medicinal use of muskmelon base (Pedicellus Melo.) for abdominal distention and constipation.

ETHNOPHARMACOLOGICAL RELEVANCE: Muskmelon base (Pedicellus Melo.) has a long history (Ming Dynasty) as a Chinese traditional medicine. According to traditional use, it was prepared as rectal suppositories for treating abdominal distention and constipation. The present study was carried out on the pharmacological basis for the medicinal use of muskmelon base. AIM OF THE STUDY: The objective of this study was to determine the pharmacological basis for the medicinal use of the ethanol extract from muskmelon base (EMB) for abdominal distention and constipation. MATERIALS AND METHODS: In this study, we report the gastrointestinal prokinetic action of EMB following single rectal or large intestinal administration. Laxative activity, gastric emptying and small intestinal transit tests were examined in ICR mice. SD rats were used to determine changes in large intestinal transit and contractile effects of the proximal colon in vivo. Guinea pigs were used to evaluate the contractile effects of the proximal colon and the possible mechanism or mechanisms on proximal colon activity ex vivo. Moreover, the acute toxicity of EMB was evaluated. RESULTS: In the in vivo experiments, the acute toxicity test showed that the maximum tolerated dose (MTD) of EMB was 400 mg/kg. A laxative effect was observed in mice at different dosages (6.5, 13 and 26 mg/kg). EMB showed a dose-dependent acceleration of gastric emptying (13 and 26 mg/kg). It also promoted both small intestinal (6.5, 13 and 26 mg/kg) and large intestinal (4, 8 and 16 mg/kg) transit activity. In the SD rat model, single rectal administration of EMB (8 and 16 mg/kg) showed a significant increase in both the frequency and amplitude of proximal colon smooth muscle contractility. These increases in amplitude and frequency peaked 30-60 min after EMB administration and corresponded with the results of the laxative activity test. The ex vivo experiments showed that varying doses of EMB (11.5, 23 and 46 mg/kg) had a direct prokinetic effect that was sensitive to atropine. CONCLUSIONS: Our results show that EMB is a low dosage, fast acting drug with a large therapeutic window (4-400 mg/kg) and shows significant gastrointestinal prokinetic action after single rectal or large intestinal administration. This gastrointestinal prokinetic effect was stronger in the intestines than in the stomach. This effect was sensitive to atropine, suggesting that EMB acts mainly through cholinergic mechanisms.

Toxicity of weight loss agents.

INTRODUCTION: With the rise of the obesity epidemic in the United States over the last several decades and the medical complications seen with it, weight loss and dieting have become a national public health concern. DISCUSSION: Because of their increased use and availability through internet sales, several different dieting agents were reviewed for potential toxicity. These included: syrup of ipecac, cathartics, human chorionic gonadotropin hormone, 2,4 Dinitrophenol, guar gum, phenylpropanolamine, ma huang/ ephedra, caffeine, clenbuterol, fenfluramine, sibutramine, thyroid hormone, orlistat and cannabinoid antagonists. CONCLUSIONS: With the internet making even banned products readily accessible, healthcare providers need to be aware of the potential toxicities of a wide range of weight loss agents. Our review covered topics we thought to be most historically significant as well as pertinent to the practice of medical toxicology today.

In-vivo laxative and toxicological evaluation and in-vitro antitumour effects of Mitracarpus frigidus aerial parts.

OBJECTIVES: To evaluate the in-vitro antitumour properties, and the in-vivo laxative and toxicological effects of the methanolic extract of the aerial parts of Mitracarpus frigidus (MFM). METHODS: The in-vitro antitumour activity of MFM was evaluated against three human tumour cell lines: Jurkat, HL60 and MCF-7. The laxative activity and the effect of MFM on intestinal motility were evaluated in rats at the doses of 100, 300 and 1000 mg/kg. Acute oral toxicity was performed at 10, 100, 1000 and 2000 mg/kg and subchronic toxicity was evaluated at 100, 300 and 1000 mg/kg of MFM during a 42-day period. After subchronic administration of MFM the biochemical, haematological and histopathological parameters were analysed. Also, the total content of anthraquinones was determined. KEY FINDINGS: MFM was cytotoxic only against HL60 and Jurkat cells with 89 and 83% growth inhibition, respectively. The laxative activity of MFM was similar to bisacodyl. Regarding the effect on intestinal motility, MFM showed a significant increase in the pathway of charcoal compared with the group treated with saline. Furthermore, MFM showed no in-vivo toxicity at the doses tested. Free and anthraquinone C- and O-glycosides were detected in MFM. CONCLUSIONS: MFM showed significant antitumour activity for leukaemic cells. Moreover, it presented laxative potential and no in-vivo toxicity.

The toxicology and carcinogenesis study of phenolphthalein (CAS No. 77-09-8) in genetically modified haploinsufficient p16(Ink4a)/p19(Arf) mice (feed study).

UNLABELLED: Phenolphthalein was commonly used as a laxative for most of the 20th century. The use of phenolphthalein in laxatives has decreased since 1997 when the United States Food and Drug Administration (FDA) proposed to withdraw its classification as an over-the-counter drug (21 CFR, Part 310). Phenolphthalein has been previously evaluated in 2-year carcinogenicity studies by the National Toxicology Program (1996). The major route of human exposure to phenolphthalein is via ingestion, dermal contact, and inhalation of contaminated air originating from process units manufacturing the compound. In this study, the carcinogenic effects of phenolphthalein were studied in the haploinsufficient p16(Ink4a)/p19(Arf) mouse model as an ongoing goal of the NTP is to seek model systems for toxicology and carcinogenesis studies, especially those that can provide mechanistic information relative to understanding an agent's mode of action. Male and female haploinsufficient p16(Ink4a)/p19(Arf) mice were exposed to phenolphthalein (greater than 97% pure) in feed for 27 weeks. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. 27-WEEK STUDY IN MICE: Groups of 15 male and 15 female mice were exposed to 0, 200, 375, 750, 3,000, or 12,000 ppm phenolphthalein (equivalent to average daily doses of approximately 35, 65, 135, 540, and 2,170 mg phenolphthalein/kg body weight to males and 50, 90, 170, 680, 2,770 mg/kg to females) in feed for 27 weeks. Survival of all exposed groups of male and female mice was similar to that of the control groups. Mean body weights of males in the 12,000 ppm group were less than those of the control group after week 11. No differences in feed consumption were noted between exposed and control groups. Atypical hyperplasia of the thymus, a premalignant change of chemically induced thymic lymphoma, occurred in exposed males and females, and the incidence was significantly increased in 12,000 ppm females. Atrophy of the seminiferous tubules in the testis, hyperplasia of the testicular interstitial (Leydig) cells, and epididymal hypospermia occurred in most 3,000 and 12,000 ppm males. Additionally, the left and right testis weights, the left epididymis weights, sperm motility, the numbers of spermatid heads per testis, and sperm heads per cauda and per gram cauda epididymis were generally significantly less in 3,000 and 12,000 ppm males than in the control group. The incidences of nephropathy were significantly increased in 3,000 and 12,000 ppm males; incidences of hypertrophy of renal tubules were significantly increased in males receiving 750 ppm or greater. Hematopoietic cell proliferation of the spleen occurred in all 12,000 ppm males, and the incidences of this lesion were significantly increased in 375, 750, and 12,000 ppm females. GENETIC TOXICOLOGY: The frequency of micronucleated erythrocytes was assessed at four time points during the 27-week study in male and female haploinsufficient p16(Ink4a)/p19(Arf) mice. Significant concentration-related increases in micronucleated cells were observed at all time points in male and female mice. CONCLUSIONS: Under the conditions of this 27-week feed study, there was no evidence of carcinogenic activity of phenolphthalein in male or female haploinsufficient p16(Ink4a)/p19(Arf) mice exposed to 200, 375, 750, 3,000, or 12,000 ppm. Because this is a new model, there is uncertainty whether the study possessed sufficient sensitivity to detect a carcinogenic effect. Phenolphthalein induced atypical hyperplasia, a preneoplastic lesion of the thymus, in male and female mice, hematopoietic cell proliferation of the spleen in male and female mice, and toxicity to the kidney and reproductive system in male mice.